Reflux
In some humans, the lower esophageal sphincter (LES) is prone to relaxing more frequently than in other humans. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or by reducing esophageal acid exposure by enhancing esophageal clearance, lower esophageal sphincter tone and gastric emptying. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, recent research (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, 517-535) has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESR), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
Consequently, there is a need for compounds which reduce the incidence of TLESR and thereby prevent reflux. Ideally, the compound should have an effect duration of approximately 12 h. since most reflux occurs during daytime and postprandially.
A pharmaceutical composition comprising a local anaesthetic, adapted to inhibit relaxation of the lower esophageal sphincter, is disclosed in WO 87/04077 and in U.S. Pat. No. 5,036,057.
GABA.sub.B Receptor Agonists
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABA.sub.A and GABA.sub.B receptor subtypes. GABA.sub.B receptors (for a review see Kerr, D. I. B. and Ong, J. (1995) Pharmac. Ther. vol. 67, pp.187-246) belong to the superfamily of G-protein coupled receptors. GABA.sub.B receptor agonists are described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome and as prokinetic and anti-tussive agents. GABA.sub.B receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680).
The GABA.sub.B receptor agonist baclofen (4-amino-3-(4-chlorophenyl)butanoic acid) (Swiss patent No. CH 449,046) has been the most studied of the GABA analogs. ##STR1##
Other GABA.sub.B receptor agonists or partial agonists are disclosed in: EP 0356128; EP 0181833; EP 0399949; EP 0463969; and FR 2,722,192. For a review on the chemistry of GABA.sub.B modulators, see Froestl, W. and Mickel, S. J. in: The GABA Receptors, pp.271-296 (Eds. S. J. Enna and N. G. Bowery, Humana Press Inc., Totowa, N.J., U.S.A. 1997)
It is known in the art that drug screening can be improved by using cells which are transfected with a cloned receptor gene. Such transfected cells may offer several advantages over traditional screening, the most important being presumably selectivity. Another advantage of transfected cells is that they allow assessment of the activity of drugs on cloned human receptors. The fact that the GABA.sub.B receptor has recently been cloned (Kaupmann et al., Nature 386(6622), 239-246, Mar. 20, 1997) thus offers the opportunity to develop more specific drugs acting on the GABA.sub.B receptor. The said article discloses two subtypes of the receptor from rat, designated GABA.sub.B R1a and GABA.sub.B R1b, but it was made very clear that several other subtypes could be isolated.